Clinical Focus Clinical Focus - Immune Deficiency Foundation

ISSUE 16
|
JUNE 2015
IDF MEDICAL ADVISORY COMMITTEE
Rebecca Buckley, MD - Chair
Duke University School of Medicine, Durham, NC
Kathleen Sullivan, MD, PhD - Vice Chair
Children’s Hospital of Philadelphia, Philadelphia, PA
Zuhair Ballas, MD
University of Iowa, Iowa City, IA
Mark Ballow, MD
University of South Florida, Tampa, FL
R. Michael Blaese, MD
Consulting Medical Director IDF, Towson, MD
Francisco Bonilla, MD, PhD
Boston Children’s Hospital, Boston, MA
Fabio Candotti, MD
National Institutes of Health, Bethesda, MD
Mary Ellen Conley, MD
University of Tennessee, Memphis, TN
Charlotte Cunningham-Rundles, MD, PhD
Mt. Sinai Medical Center, New York, NY
Alexandra Filipovich, MD
Cincinnati Children’s Hospital, Cincinnati, OH
Thomas Fleisher, MD
National Institutes of Health, Bethesda, MD
Lisa Forbes, MD
Texas Children’s Hospital, Houston, TX
Ramsay Fuleihan, MD
Ann & Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL
Erwin Gelfand, MD
National Jewish Medical and Research Center,
Denver, CO
Vivian Hernandez-Trujillo, MD
Miami Children’s Hospital, Miami, FL
Steven Holland, MD
National Institutes of Health, Bethesda, MD
Howard Lederman, MD, PhD
Johns Hopkins Hospital, Baltimore, MD
Harry Malech, MD
National Institutes of Health, Bethesda, MD
Stephen Miles, MD
All Seasons Allergy, Asthma & Immunology,
The Woodlands, TX
Luigi Notarangelo, MD
Boston Children’s Hospital, Boston, MA
Hans Ochs, MD
Seattle Children’s Hospital, and University of
Washington, Seattle, WA
Jordan Orange, MD, PhD
Texas Children’s Hospital, Houston, TX
Jennifer Puck, MD
University of California, San Francisco,
San Francisco, CA
Sergio D. Rosenzweig, MD, PhD
National Institutes of Health, Bethesda, MD
John Routes, MD
Children’s Hospital of Wisconsin, Milwaukee, WI
William Shearer, MD, PhD
Texas Children’s Hospital, Houston, TX
E. Richard Stiehm, MD
UCLA School of Medicine, Los Angeles, CA
Troy Torgerson, MD, PhD
Seattle Children’s Hospital, Seattle, WA
James Verbsky, MD, PhD
Medical College of Wisconsin, Milwaukee, WI
Jerry Winkelstein, MD
Professor Emeritus Johns Hopkins University
School of Medicine
Clinical Focus
on primary immunodeficiencies
Subcutaneous
Immunoglobulin
Replacement
Authors
Francisco A. Bonilla, MD, PhD
Carla Duff, CPNP, MSN, CCRP
Editor
Mark Ballow, MD
This publication was made possible by
an educational grant from CSL Behring.
www.cslbehring.com
This book contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice
can change rapidly. Therefore, this book should not be used as a substitute for professional medical advice.
Immune Deficiency Foundation Clinical Focus on Primary Immunodeficiency: Subcutaneous Immunoglobulin Replacement
Copyright 2015 by Immune Deficiency Foundation, USA.
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Subcutaneous Immunoglobulin Replacement
Authors
improved, Ig products suitable for intravenous
1
Francisco A. Bonilla, MD, PhD
Carla Duff, CPNP, MSN, CCRP2
1
Director, Clinical Immunology Program,
Boston Children’s Hospital, Boston, MA
Associate Professor of Pediatrics,
Harvard Medical School, Boston, MA
administration (IVIG) became available in the 1980’s.
These products are well-tolerated by a majority of patients.
However, some patients have systemic side effects
(discussed further below) during or after infusion. In
addition, some patients experience the cyclical rise and
fall of IgG levels between intravenous infusions as cyclical
periods of relative malaise when IgG levels are low.
2
Advanced Registered Nurse Practitioner,
University of South Florida, St. Petersburg, FL.
Address:
Boston Children’s Hospital
300 Longwood Avenue
Boston, MA 02115
Phone: (617) 355-8594
Fax: (617) 730-0310
Email: francisco.bonilla@childrens.harvard.edu
University of South Florida
601 5th Street South, 3rd Floor
St. Petersburg, FL 33701
Phone: (727) 727-4150
Fax: (727) 767-8532
Email: cduff@health.usf.edu
Subcutaneous administration of Ig (SCIG) is associated
with minor local side effects and fewer systemic effects in
comparison to IVIG. It is administered without the need for
IV access and usually in smaller and more frequent doses
so that the IgG level in the body remains relatively
consistent, without the fluctuation characteristic of IVIG
given every 3 or 4 weeks.
Use of SCIG has continued to grow slowly in the U.S.
since the Food and Drug Administration (FDA) approved
the first product intended for subcutaneous
administration 2. Several products (described below) now
have FDA approval for subcutaneous administration and
SCIG accounts for an increasing fraction of Ig replacement
therapy.
Ig products originally formulated for intravenous use can
also be administered via the subcutaneous route, and
Introduction
some of these products have been approved by the U.S.
The first published therapeutic use of human Ig appeared
Food and Drug Administration (FDA) for both routes of
in the medical literature in 1952 1. Colonel Ogden Bruton
administration. Some products have been formulated
gave subcutaneous infusions of Ig to a boy with
specifically for subcutaneous use and cannot be
agammaglobulinemia and showed that the serum
administered IV. One of these products has entered the
electrophoresis gamma globulin peak became detectable
market very recently and represents a novel technique of
and the frequency and severity of bacterial infections was
subcutaneous administration facilitated by prior infusion of
diminished. Purified polyclonal human Ig for general
recombinant human hyaluronidase. In this guideline, any
therapeutic use has been available since the 1960’s.
Ig administered by the subcutaneous route will be referred
to as SCIG, with the exception of the hyaluronidase-
Intramuscular injection of Ig is painful, and it is difficult to
facilitated product which will be referred to as Hy-SCIG.
administer amounts of Ig intramuscularly sufficient for
protection from infection. As Ig purification methods
Immune Deficiency Foundation: Clinical Focus / 1
Pharmacokinetics of Ig Administered
by the Intravenous and Subcutaneous
Routes
Immediately following an IVIG infusion of approximately
(Figure 1). This has been shown to result in essentially
constant serum Ig concentrations over time. The
pharmacokinetics of Hy-SCIG is intermediate between
IVIG and SCIG, with a blunted broad early peak of
concentration and a trough similar to IVIG (Figure 1).
300-500 mg/kg, the serum IgG level increases 2-fold or
more since the entire dose is in the intravascular space
(Figure 1) 3. Over the subsequent 48-72 hours, Ig diffuses
out of the circulation into extravascular spaces, and
eventually equilibrates into a volume of distribution
approximately equal to the total extracellular fluid.
Following this equilibration phase, the Ig is catabolized
with first order kinetics and a half-life of about 21 days.
Note that this is an average half-life of physiologic Ig in the
circulation. Measured average half-lives of Ig in clinical
The area under the curve of a plot of serum Ig
concentration (Y-axis) vs time (X-axis) (Figure 1) is a
measure of the bioavailability of an infused Ig product 3.
The bioavailability of SCIG is approximately 2/3 in
comparison to the same amount of Ig administered IV 7.
This may be taken into account when prescribing an Ig
replacement regimen. This will be discussed further
below. The bioavailability of Hy-SCIG is approximately
93% of IVIG and they are considered bioequivalent 4-6.
trials are usually longer with significant variation between
products ranging from 28-45 days, particularly in
Figure 1.
immunodeficient patients. It is also critical to note that
Kinetics of Serum IgG Levels
there is tremendous variation between individuals. In
Pharmacokinetics figure from Wasserman RL, Melamed I,
Stein MR, Gupta S, Puck J, Engl W, et al. Recombinant
human hyaluronidase-facilitated subcutaneous infusion of
human immunoglobulins for primary immunodeficiency. J
Allergy Clin Immunol. 2012;130(4):951-7 e11.
clinical trials of IVIG, even with a single preparation,
variation in serum Ig half-life between individuals can be
as high as 6-fold (range 15-88 days) 3.
IVIG is usually given at a 3 or 4 week dosing interval.
During this period, the range of Ig concentrations from
peak to trough usually varies by 250 to 300% of the
trough values (Figure 1). In contrast to the high peaks
achieved after periodic IV infusions, most SCIG regimens
fractionate the monthly dose into smaller increments
which are given every 1-14 days 3. Hy-SCIG is distinct;
Hy-SCIG is designed to be used in regimens more similar
to IVIG administered every 3-4 weeks 4-6.
Following a subcutaneous Ig infusion, the equilibration of
the Ig into its eventual volume of distribution is achieved
by diffusion into the lymphatics from the local site, into the
vascular space, then out again into extravascular spaces
throughout the body. Ig is absorbed from a subcutaneous
infusion site over the course of a week, with most of the
absorption occurring in the first 48 hours. Thus, the high
peaks seen with intermittent larger IV infusions are
markedly truncated. With weekly or more frequent SCIG
infusions, the range of serum Ig concentrations from peak
to trough may vary by less than ± 10% around the mean
2 / Immune Deficiency Foundation: Clinical Focus
Efficacy, Safety, and Tolerability of Ig
Administered by the Intravenous and
Subcutaneous Routes
2) no plateau with respect to the decrease rate of all
reported infections in relation to the steady-state IgG
level.
Note that Ig is generally dosed according to total body
Efficacy
mass. Retrospective studies indicate that this is
For replacement therapy for immunodeficiency, most Ig
appropriate13. Individuals with high BMI do not have
clinical trials focus on patients with XLA and common
greater or lesser increases in IgG levels with IVIG or SCIG
variable immunodeficiency (CVID). All FDA-approved Ig
in comparison to those with low BMI when dosed
products meet a standard of efficacy. In the U.S., efficacy
according to total body weight. Thus, it is not appropriate
is judged by the incidence of acute serious bacterial
to use ideal body weight or lean body mass as a
infections (SBI) per patient per year 8. The FDA has
denominator for Ig dosing. The retrospective studies
defined rigorous criteria for diagnosing the infections fitting
cited 13 suggest that such an approach would likely lead to
into this classification, which include bacteremia/sepsis,
under-dosing.
pneumonia, visceral abscess, osteomyelitis/septic arthritis,
and bacterial meningitis. The minimal acceptable criterion
Safety
for licensing of a new Ig product in the U.S. is that the
IV and SC products/routes are also generally equivalent
upper bound of the 99% confidence interval around the
with respect to safety (mainly lack of disease transmission).
mean for the annual incidence of these infections in
Several Ig products are FDA-approved for both IV and SC
patients with XLA and/or CVID must be <1 (in most trials it
administration (Table 1). Note that Hizentra® and HyQvia®
is much lower).
are formulated only for SC use and cannot be given IV. All
Ig products available in the U.S. are made solely from
A meta-analysis of clinical trials of Ig replacement showed
a number of important findings 9. First, trough IgG levels
increase more or less linearly with cumulative dose up to
approximately 1 g/kg/month. There is no plateau or
diminishing slope with higher doses up to this limit. Even
more important, there is a linear decrease in the incidence
of pneumonia with increasing trough IgG level up to the
same dose limit. There is no “point of diminishing returns”
with respect to benefit with increasing dose. This likely
reflects the fact that some individuals require relatively
higher doses of Ig for clinical benefit in comparison to
plasma collected from carefully screened and tested U.S.
donors, and all of the manufacturing procedures include
steps which have been shown to inactivate and/or partition
multiple types of viruses 14. There is no evidence to suggest
that the risk of acquiring blood borne viruses or prions
varies with SC vs. IV administration. There are no reported
cases of disease transmission by SCIG, and none with IVIG
since 1994 15. None of the Ig preparations currently
available in the U.S. contains thimerosal or other mercurycompound preservatives. However, contraindications,
precautions and warnings can differ among products.
others 10. Higher dosing might be needed for other comorbidities such as bronchiectasis and protein losing
Rare cases of anaphylaxis during IVIG administration have
enteropathies.
been reported in association with IgG anti-IgA antibodies in
patients with IgA deficiency 16, 17. (Note that there is a
Several studies suggest that Ig administered
single published report of anaphylaxis in association with
subcutaneously is at least equal in efficacy to Ig
IgE anti-IgA antibody 18.) SCIG contains small amounts of
11
administered intravenously , even though there have not
IgA, comparable to several preparations of IVIG. There are
been direct comparisons of the same Ig preparation given
no published reports of anaphylaxis with SCIG in patients
by the different routes. A meta-analysis of SCIG trials very
with IgA deficiency. In fact, patients who have had
similar to the study reported for IVIG above 9 led to very
anaphylactic reactions with IVIG (whatever the mechanism
similar conclusions 12. That is:
may have been), have tolerated SCIG16, 17. Although all Ig
1) no plateau effect of steady-state IgG level in relation to
cumulative dose, and
products (IVIG and SCIG) carry the same warning related
to use in patients with IgA deficiency, it should be
Immune Deficiency Foundation: Clinical Focus / 3
emphasized that anaphylaxis by any mechanism is a very
Ig, especially anti-A 21. Risk factors include pre-existing
rare event with any form of Ig therapy, including patients
hemolytic disease, inflammatory states, and rapid high
with IgA deficiency. This is a potential concern only in
dose infusions. Rare cases of acute renal failure and
patients with absent IgA (i.e., below the limit of detection
death have been reported. Current US and EU standards
or <5-7 mg/dL) and who have high levels IgG of anti-IgA
require isoagglutinin titers <1:64 21.
18
antibody .
Tolerability
Thrombotic events are a rare complication of Ig therapy,
Adverse events differ somewhat between IVIG and SCIG23, 24.
occurring in approximately 0.1% of treated individuals
Most patients tolerate IVIG without side effects and do not
overall
19, 20
. These occur more often with rapid high-dose
IVIG infusions, but they have been reported with SCIG as
require pre-medication. However, in 10-25% of patients
there are mild side effects that occur during or soon after
well. This complication is thought to arise primarily from
infusion. These symptoms can include headache, back or
activated clotting factor XIa which is a contaminant
abdominal pain, malaise, nonspecific or urticarial rashes,
present to varying degrees in Ig preparations. Patients at
and cough. About 5% of patients have more severe
highest risk have a history of prior thrombosis or vasculitis
symptoms that may mimic hypersensitivity reactions or flu-
or other factor predisposing to risk of thrombosis.
like illness with fever, myalgia/arthralgia, rhinorrhea, and
wheeze. Perhaps 1% or fewer patients will have severe
Hemolysis may also occur in association with Ig therapy,
rigors, or a presentation similar to aseptic meningitis that
either IV or SC21, 22. Clinically significant hemolysis is
appears 24-72 hours after infusion. The great majority of
estimated to occur in approximately 1:10,000 infusions;
these symptoms are relatively easily controlled with pre-
recognition may be delayed >24 hr. Anemia can be severe
hydration, slow infusion, non-steroidal anti-inflammatory
enough to require transfusion. Hemolysis is seen with
drugs, antihistamines, and occasionally corticosteroids.
much greater frequency with IVIG in comparison to SCIG.
Anaphylaxis with IVIG is very rare (<1:10,000 infusions)
Hemolysis is due to isoagglutinins present in therapeutic
and has not been reported with SCIG.
Table 1
Ig products and FDA-approved routes of administration
Product
Intravenous
Subcutaneous
Yes
No
Yes
No
Flebogamma
Yes
No
Gammagard Liquid®
Yes
Yes
Gammagard SD®
Yes
No
Gammaked®
Yes
No
Gammaplex®
Yes
No
®
Yes
Yes
No
Yes
No
Yes
Octagam
Yes
No
®
Yes
No
®
Bivigam
Carimune
®
®
Gamunex-C
Hizentra
HyQvia
®
®
®
Privigen
4 / Immune Deficiency Foundation: Clinical Focus
Systemic symptoms are less frequent in patients receiving
considered painful or serious. Some patients may experience
SCIG23, 24. The relative freedom from systemic effects of
swelling without erythema, or vice versa (Figure 3). Often,
subcutaneously administered Ig is likely due, at least in
adjustment of ancillary supplies will mitigate site reactions
part, to the slower absorption and equilibration of the Ig
(Figure 4). The swelling and erythema almost always
into the circulation. In contrast to the freedom from
dissipate completely within 24 hours after the infusion is
systemic adverse effects, the incidence of local reactions
finished. In most cases, by 72 hours, it is difficult to
at the infusion sites may be quite high, particularly when
identify the site at which subcutaneous Ig was given.
patients first begin to use the subcutaneous route. Rates
of local reactions as high as 80-90% with initial
The severity of these types of reactions and the incidences
subcutaneous infusions have been recorded, although the
with which they occur have been reported to decrease
incidence of these reactions falls below 30% within 1-2
dramatically as the patient continues with SCIG23, 24. The
months of continued weekly subcutaneous treatments.
reasons for this are not clear. Certainly, there is some
Local reactions (Figure 2) often include swelling, which in
they may report decreased severity as they “get used” to
subjectivity in the patient’s reporting of symptoms, and
some cases may seem to be bigger than the volume of Ig
these local reactions. However, objective signs of site
infused depending on distribution of subcutaneous tissue,
reactions also seem to improve with time. Examination of
and erythema. Sometimes there can be a sensation of
patients who have used the subcutaneous route for many
burning or itching 23, 24. These local reactions are rarely
years fails to reveal any chronic local change in the tissues
such as fibrosis or lipodystrophy. Some patients may
develop isolated hard nodules or “pearls” below the sites
Reactions at sites of Subcutaneous
Infusions
of individual infusions but these are usually not tender,
and usually regress spontaneously over a few weeks or
months. Infusion into sites with nodules should be avoided
Figure 2.
in order to hasten resolution. Local adverse effects of Hy-
Slight Erythema and Swelling During Infusion
SCIG are comparable to SCIG 4-6. Systemic symptoms after
Infant receiving subcutaneous Ig into site on left thigh.
Note typical amount of swelling and erythema. Baby is
not bothered by this and carries on playing.
Hy-SCIG are greater than with SCIG, but less than what is
observed after IVIG.
Effects on Quality of Life for Patients
with Primary Immunodeficiency
Disease (PI)
Because the volume of Ig that can be comfortably and
conveniently infused SC at one time is limited, most SCIG
regimens fractionate the total monthly Ig dose into 4 or
more infusions, which are given weekly or more
frequently. Volumes can vary dramatically based on
frequency, concentration, and dosage with ranges from
1-50 mL with SCIG and from 50-600 mL per site with
Hy-SCIG. Low dose daily infusions are also possible and
preferred by some patients 25, 26.
Since the subcutaneous route has a very low risk of
serious systemic reactions, self, partner or parent
administration of SCIG at home is routine. The freedom
(Photo courtesy D. Sedlak, Duke University)
from dependence on trained medical personnel and/or
Immune Deficiency Foundation: Clinical Focus / 5
Reactions at sites of Subcutaneous Infusions
Figure 3.
Subcutaneous Infusion (SCIG)
24 hours post infusion
8 hours post infusion
0 minutes post infusion
(Reprinted with permission from CSL Behring, LLC)
Figure 4.
SCIG Initial Regimen
Initial SCIG regimen
Technical or clinical complaints?
NO
YES
Adjust ancillary supplies:
• Skin preparation
• Tape
• Transparent dressing
YES
Consider administration
parameters:
• Volume
• Flow rate
• Site of infusion
• Number of infusion sites
YES
Continued complaints?
Adjust ancillary supplies:
• Subcutaneous needle set
length and diameter
• Infusion pump device/syringe
driver
• Change SCIG needle
(length/gauge, type/brand)
Continue evaluation: tolerability generally increases over time
6 / Immune Deficiency Foundation: Clinical Focus
special facilities for routine Ig treatments is appreciated by
(wear off effect). The second set includes factors which
most patients. Several quality of life studies have been
have more to do with the patients’ perception of their
performed 27. In at least 7 such studies, quality was
quality of life than with their clinical condition. Decisions
significantly better with SCIG compared to IVIG.
for treatment options should be individualized based on
Dimensions that were improved with SCIG included
each patient’s medical condition(s) as well as patient
global/general health, bodily pain, role social/emotional
input. Full involvement of patients in their treatment
and physical, parental impact/emotional and time, family
decisions has the potential to improve compliance and
activities, vitality, mental health and social functioning.
adherence resulting in improved quality of life and patient
outcomes. A recent study by Samaan et al. demonstrated
Studies are limited, but some suggest that SCIG may also
engaging the patient and empowering patient choice
be more cost effective than IVIG 28.
without preconceived opinions resulted in a high rate of
Patient Selection
There are two sets of considerations which contribute to
compliance 29.
That said, when patients are given more control over their
the decision as to which route of therapy might be best for
management and feel more empowered, they may also be
any individual patient with PI in any given set of
free to make poor decisions about changes in their
circumstances (Table 2). The first set is comprised of
infusion schedules, or may be less adherent to their
clinical factors which might make SCIG preferable, such
regimen, overall. Regular follow-up visits with specific
as problems in obtaining IV access, intolerability from
questioning about any lapses or changes in the dose
relatively large intermittent IV doses, and suboptimal
regimen together with more frequent monitoring of IgG
clinical conditions resulting from low Ig serum trough level
levels are necessary to insure adherence.
Table 2
Considerations in Selecting Route of Ig Therapy
Clinical Factors Favoring SCIG
• Difficult IV access
• Systemic adverse effects during or after IV infusions
• Adverse effects/suboptimal health at trough when IV infusion due
• Risk for thromboembolic events or hemolysis
Lifestyle/Psychological Factors in Choosing Route of Administration
• Patient/family preference
• Distance from/accessibility of infusion center
• Patient/family schedule
• Availability of home nursing services
• Ability to learn and perform infusions
• Availability of partner/parent/“infusion buddy”
• Home environment
• Reliability of patient or parents
• Insurance/reimbursement issues
Immune Deficiency Foundation: Clinical Focus / 7
Developing Individualized Treatment
Regimens
Ig Dose for Replacement
The decrease in systemic adverse reactions and lack of
patient requires between 300 and 800 mg/kg body weight
requirement for trained healthcare professionals allows
via IV (or Hy-SCIG) infusion. Most patients do well in the
On a monthly basis, the “average” hypogammaglobulinemic
great flexibility in the choice of the SCIG regimen to be
0.4-0.6 g/kg range, some can get by with less and others
used for any given patient. For example, some patients
require more. The keys are to individualize the dose and
prefer taking infusions slowly into a single site while they
titrate to clinical outcomes. Recall that Ig half-life varies
sleep. Other patients prefer multiple sites and a short
greatly between individuals. It is critical to follow patients’
infusion time weekly or less. Others may prefer to use a
IgG levels and clinical course closely when initiating or
small amount in a single site more frequently, even daily,
modifying the regimen.
etc. Considerations for SCIG regimens are summarized in
As mentioned above, the bioavailability of SCIG is less
(Table 3). Note again that the dosing regimens for Hy-
(about 2/3) in comparison to the same amount
SCIG are intended to be parallel with IVIG.
administered IV. Thus, when changing a patient
established on IV therapy to SC, the monthly amount may
be increased by a factor of approximately 1.3. However,
Table 3
Interrelated Variables to be Considered in Selecting a Regimen for Subcutaneous Ig Infusions.
Cumulative monthly dose
• Initial therapy: 0.6-0.7 g/kg body weight
• Switch from IV: 1.3 X IV dose
Infusion dose and interval
• Interval may range from daily to every 2 weeks
• Infusion dose depends on interval to make up monthly total
• ALWAYS USE UNIT DOSES!
Number of infusion sites
• Depends on BMI
• Low BMI: 5-10 cc/site
• Medium BMI: 10-20 cc/site
• High BMI: 20-50 cc/site
• Larger volumes may be accommodated with longer (>1 hr) infusion times
Infusion time
• 5-20 min. for small infusions (5-20 cc)
• 30-60 min. for larger/multi-site infusions
• >60 min. to accommodate larger volumes in fewer sites
Infusion method
• Push by hand for small (5-20 cc) single-site infusions
• Pump for larger multi-site infusions
8 / Immune Deficiency Foundation: Clinical Focus
there is considerable variability in opinion about this, with
because of the two drug regimen and the different type of
many providers choosing to use the same dose that was
tubing needed. Just as Ig dosing must be individualized to
given IV. When initiating SCIG therapy for a patient who
achieve therapeutic clinical outcomes, so should the SCIG
has never received Ig before, consider a monthly dose of
regimen be individualized to optimize frequency, infusion
600-700 mg/kg. Several studies suggest improved
rate and site selection for best outcomes. Below are some
outcomes with higher SCIG doses12, 30, 31.
examples of individualizing SCIG therapy 34, 35.
When a patient is initiating SCIG therapy and it is desired
Examples
to bring the IgG level into a steady state as quickly as
1) A 10 kg child is starting SCIG at a dose of roughly 7 g
possible, one may consider administering (a) loading
Ig (700 mg/kg) monthly. This could be given as 1 g
dose(s) either by IV or SC. A typical IV loading dose would
every 4 days, 2 g every 8 days, or 3 g every 12 days.
be 1,000 mg/kg (roughly the total amount of IgG in a
Remember, use unit doses only! For an Ig product with
healthy adult). The replacement SCIG dose may be given
a concentration of 20%, a 1 g dose has a volume of 5
on the same day, or within one week following the loading
cc and can be given in a single site over 30 minutes or
dose. Smaller loading SCIG doses may be given on 3-5
less. Even a 2 g (10 cc) dose might be accommodated
consecutive days to reach the cumulative 1 g/kg total
in a single site with a slower infusion time. The 3 g
loading dose followed immediately by the replacement
(15 cc) dose might need to be split into 2 sites, if the
regimen.
child is slender. If one is using a product with 10%
concentration, then the volumes will be double for the
The dose interval for SCIG can be anywhere from 1-14
same dose. In this example, the highest dose/volume
days. Note that therapeutic Ig is a precious commodity
would be 3 g or 30 cc which might need to be given in
that should not be wasted, it is never appropriate to use a
3 sites, depending on the infusion time.
fraction of a unit dose and discard the remainder. The
dose interval can always be adjusted, if necessary. With
2) A 40 kg child is doing well on IVIG and wants to switch
the variety of dosage forms available, almost any product
to SCIG. The current regimen is 20 g (500 mg/kg)
can be used with great flexibility.
monthly. You wish to give roughly 1.3 x 0.5 g/kg = 650
mg/kg or 26 g monthly. A 20% solution could be given
Areas of the body commonly used for infusion are those
as 5 g every 6 days or 10 g every 12 days. One could
with some subcutaneous tissue such as the abdomen,
also choose to start at a lower cumulative dose such as
inner thighs, flanks, buttocks, and the posterior upper
5 g weekly or 10 g every 2 weeks. This could even be
arm. It is recommended to rotate the sites used with each
given as 1 g daily on any 5 days per week. If the patient
infusion. The number of sites to use for infusion and the
doesn’t do well, the dose can be increased to 6 g
amount to infuse in each site are a function of the body
weekly or 12 g every 2 weeks, etc. Considerations of
mass index, the infused volume and the speed of infusion.
number of sites and volume per site again depend on
A slender individual cannot accommodate a large
concentration (double volumes for 10% solution), BMI,
subcutaneous infusion. A single site may only comfortably
and rapidity of infusion, as discussed above.
receive 5-20 cc. An overweight individual can tolerate up
to 30-50 cc in one site. Smaller volumes may be infused
3) A 70 kg adult is established on 35 g every 3 weeks
rapidly in 15-30 minutes, larger volumes more slowly (1-2
IVIG, or approximately 44 g monthly. You switch to SCIG
hours or more). SCIG is appropriate for all ages. Neonates
at a dose of roughly 1.3 x 44 = 57 g monthly. A 20%
and infants can receive SCIG (SCIG products have not
solution could be given as 2 g (10 cc) daily, 4 g (20 cc)
been studied in licensing trials below 2 years old; Hy-SCIG
every other day, 7 g (35 cc) twice per week, 14 g
and Gamunex-C are licensed for use in adults only) 32, 33.
(70 cc) weekly, 20 g (100 cc) every 10 days or 28 g
In fact, SCIG may be preferable in infants, young children
(140 cc) every 2 weeks. This patient decides that they
and geriatrics since IV access is not required.
like the daily dose because they can give it to
Administration of Hy-SCIG can be more complicated
themselves in a single site in 10-15 minutes.
Immune Deficiency Foundation: Clinical Focus / 9
SCIG Therapy in Practice
expectations tend to be more compliant and have more
The management and treatment of PI is a complex
positive outcomes 29, 34, 36.
process that may be difficult for some patients. Prior to
initiating SCIG therapy, the treatment options including
routes, frequency, volume, and brands as well as the
advantages and disadvantages for each option need to be
discussed with the patient. This should be a frank and
open discussion without bias and allow for collaboration in
the decision making. When patients are part of the
decision making process, they are more likely to be
compliant and have a positive outcome 29, 36.
The patient should expect that an educated and
experienced infusion nurse will be providing their SCIG
training. In addition to discussing expectations, the nurse
will provide education regarding self-administration skills
and provide individualized learning tools for each patient
receiving SCIG therapy. The patient will be expected to
demonstrate proficiency to the infusion nurse, and it may
take 3-4 training sessions for the patient to feel
comfortable to perform the infusion alone 34, 35.
SCIG therapy has many advantages over IVIG including
flexibility of administration, steady state Ig levels, and
During the training sessions, it may be helpful for a
patient autonomy. As SCIG does not require IV access, the
parent, partner, or friend to be present to learn the self-
patient can perform the infusion anywhere, anytime. Since
administration process to offer support and assistance
SCIG is gradually absorbed, systemic adverse reactions
when the patient performs the infusions. As patients must
due to a large increase in Ig levels typically associated with
be proficient in infusion preparation, infusion set up and
IVIG (including headaches) are not as common with SCIG.
administration, and infusion supply disposal, the teaching
The disadvantages associated with SCIG include more
steps for each section will be tailored to the individualized
frequent dosing and whether the patient is willing or able
regimen for the patient. Patients must also demonstrate
to perform the infusion. As new products have emerged
proficiency in hand washing, aseptic technique, proper
with different dosing intervals, SCIG can now be
use of equipment, proper storage and handling of
administered weekly, biweekly, and monthly, thus
medication and supplies, disposal of medication and
supplies, and documenting the infusion in their therapy
providing options for patients.
journal or electronic personal health record, such as the
Before beginning SCIG, the patient must be informed of
IDF ePHR, designed for patients with PI. A patient may be
the benefits as well as the risk associated with Ig
deemed proficient to self-administer when the patient can
replacement therapy. Patients should be well informed
do a return demonstration without prompting or “teach” it
about therapy benefits as well as Ig therapy risks
back to the nurse. A detailed checklist of these skills
mentioned earlier: All IVIG and SCIG products have similar
should be provided to the patient as a reference tool 34, 35
warnings and contraindications such as possible renal
(see Appendix 2).
failure, thrombotic events, aseptic meningitis, hemolysis,
and anaphylactic reactions. Hy-SCIG has additional
The infusion nurse should provide the patient with
warnings regarding theoretical possible impact on male
continued support, including weekly phone calls,
32
fertility of anti-hyaluronidase antibody . Note that there
especially during the transition phase which typically lasts
has not been any such demonstrated effect, but all
3 months. If the patient should experience difficulty
relevant warnings for a particular product should be
administering SCIG, a follow up visit to observe the
discussed with the patient before initiating therapy 37, 38.
administration technique may be warranted. A discharge
instruction sheet detailing whom to call for any infusion
A discussion regarding expectations including infusion
related issues as well as a schedule for follow up visits
time, instructions for self-administration, necessary
with the provider should be provided to the patient. Most
equipment and supplies, resources available, and
importantly, the patient should be informed that often the
common side effects including site reactions should occur
regimen or ancillary supplies will need to be adjusted and
before the patient begins therapy. Patients with realistic
that they should contact the infusion nurse or their
10 / Immune Deficiency Foundation: Clinical Focus
provider to troubleshoot any SCIG infusion issues39
IVIG treatment. SCIG is suitable for self-administration
(see Appendix 1). There is a variety of educational
and does not require venous access; thus, patients no
materials and references available to the patient, infusion
longer need to schedule an appointment for each
nurse, and provider (Table 4) to ensure that the patient
infusion but instead have the flexibility to manage their
is successful performing self-administered SCIG
therapy. SCIG allows patient input for designing an
infusions.
optimal therapy regimen. However, independence from
the office/infusion suite also places increased
Summary
responsibility on the patient or parents. SCIG regimens
SCIG is as efficacious as IVIG for treatment of primary
are very flexible with respect to frequency of infusions,
immunodeficiencies. Clinical advantages include less
and many patients appreciate the increased flexibility and
systemic adverse reactions, particularly useful in patients
autonomy conferred by home subcutaneous treatment
who have experienced or are at risk for complications of
and report increased quality of life.
Table 4
Reference and Educational Materials
Reference and Educational Materials
Immune Deficiency Foundation
www.primaryimmune.org
International Patient Organization for Primary Immunodeficiencies
www.ipopi.org
Jeffrey Modell Foundation
www.info4pi.org
Baxter International Inc.
www.baxter.com
Bio Products Laboratory
www.bpl.co.uk
Biotest Pharmaceuticals Corporation
www.biotestpharma.com
CSL Behring
www.cslbehring.com
Grifols
www.grifols.com
Kedrion
www.kedrionusa.com
Octapharma
www.octapharma.com
Disclosures
Dr. Bonilla has been a consultant for Baxter, the Cowen Group, CSL Behring, the Gerson-Lehrman Group,
and Grand Rounds Health. He also receives royalties from UpToDate in Medicine, and is a member of the
Medical Advisory Committee and the Consulting Immunologist Program of the Immune Deficiency
Foundation.
Ms. Duff has served as a nurse consultant for CSL Behring and Baxter Healthcare, is a member of the
International Nursing Group for Immunodeficiencies (INGID), the Immune Deficiency Foundation Nurse
Advisory Committee, National Association of Pediatric Nurse Practitioners (NAPNAP), and American
Academy of Allergy, Asthma, and Immunology. She has received research support from CSL Behring.
Immune Deficiency Foundation: Clinical Focus / 11
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Immune Deficiency Foundation: Clinical Focus / 13
Appendix 1
Nursing Guide for Troubleshooting SCIG Administration
Leaking at Site
Extreme Discomfort with Needle
• Assess catheter: is it fixed securely?
• Assess length: may be too long and irritating to
• Assess site location needle placement. Site location
should not be subject to movement.
• Assess amount of subcutaneous tissue at injection site
and, if appropriate, consider site with more tissue.
abdominal wall.
• Consider topical anesthetic prior to insertion.
Blood Return Observed
• Do not infuse in site that has blood return. Hizentra
• Assess length of catheter: may be too short—can
should be infused into subcutaneous tissue only.
suggest catheter brand change.
• Do not administer intravenously.
• Assess volume being infused: may be too much volume
per individual site. Adjust accordingly.
• In single-site tubing, remove and discard appropriately.
Use new set. Notify supplier of need for replacement
Local Irritation (Redness, Swelling, Itching)
• Educate patients and caregivers that local reactions are
common and expected. Most are mild in nature.
• Assess size: mosquito bite, raised wheal, quarter, plum,
sets.
• In multisite sets, clamp off the tubing that shows the
blood return and then remove the catheter from that
site. Check with prescribing physician regarding
peach, grapefruit—size should be consistent with
selecting alternative for accommodating fewer sites:
volume being infused and amount of subcutaneous
o Infuse the drug with the remaining appropriately
tissue on patient; thinner patients may have more
located sites, thus increasing volume per site. May
prominent raised area; decrease amount of volume per
need to recalculate to a slower rate of infusion if
site as necessary. Adjust site location accordingly.
appropriate. Consider previous history of site
• Assess length of catheter: may be too short; can
suggest longer catheter length or brand change to
avoid discomfort.
• Assess if tape allergy: change to paper/hypoallergenic
tape.
• Assess if rotating sites appropriately: may decrease
frequency of rotation.
• Decrease volume per site and/or increase infusion time
• When priming the subcutaneous needle sets, do not
reaction and other factors.
o Infuse the original amount of volume per site with
the sites that are in place. When completed, repeat
the infusion session with new site to accommodate
the remaining volume from the site that had blood
return.
• Change entire setup and start over.
Long Infusion Times
• Check patency of tubing, number of sites, volume per
allow drops of IgG to cover needle.
site. Check site location (do not inject into skin that has
o Prime dry, leaving a small amount of air before
scar tissue).
needle. It has been suggested that the IgG tracked
• Assess infusion rate settings, correct selection of tubing
through the intradermal space can cause site
size and length to match infusion rates, check pump
reactions such as redness and itching.
function, battery function, etc.
• Advise use of gentle massage, warm or cool compress
post infusion.
• Stop the infusion if generalized urticaria is present.
Contact physician.
14 / Immune Deficiency Foundation: Clinical Focus
• Arrange observation of patient technique (specialty
pharmacy provider or office visit).
Appendix 1 continued
Needle Contaminated by Touching, Dropping, etc.
Difficulty with Manipulating Syringes for Filling
• Aseptic procedures require that supplies not be
• Lubricate the barrel of the syringe for easy manipulation
contaminated. Discard questionable needles in
by aseptically pulling back on the syringe, and moving
appropriate waste container and restart procedure.
it up and down before drawing up solution or filling with
air.
Infusion Pump Stops During Infusion
• Check battery. Check for any line occlusion. Do not
override occlusion alarm and increase psi delivered.
• Check sets for down-line occlusion. Multisite sets may
cause occlusion alarm due to codependence of lines
• Pull back the amount of air to be infused into the vial
and then attach the needle aseptically to the syringe.
• Mark the level of mL to which the syringe should be
drawn back by placing tape on the outside barrel at the
necessary level.
• Change catheter brands or use single independent lines
that equally connect off a multiextension pigtail.
• Change gauge of catheter needle.
• Change type of infusion pump to simple syringe driver
• Contact specialty pharmacy provider or supplier for
further information.
• If necessary, maintain a closed system (leaving all
connections intact), remove syringe, leave tubing
attached to site and manually push plunger forward
slowly to deliver remaining volume. Depending on
volume, this may take some time.
Immune Deficiency Foundation: Clinical Focus / 15
Appendix 2
Training Checklist for Home Administered Subcutaneous Immunoglobulin (SCIG) Infusion Treatment
Specific steps to be assessed prior to patient/caregiver considered competent to self-administer
medication in a home setting. Number of training sessions can be individualized for patients.
Patient Name:
Clinician:
Person Responsible for Infusion:
Patient
Name:
Patient Skills
Introduced
C/NYC
Date:
Initials
C/NYC
(C/NYC)
Describe transportation & storage
requirements of specific product
Define SCIG administration and location
of site of infusion
Listing of appropriate infusion sites and
understanding of rotation of sites
Understanding and demonstrated care of
infusion site
Description of appropriate supplies
necessary to complete procedure
Understanding of pump usage and what
to do when not working or if alarm
sounds
Understanding of “push” method as an
alternative or when pump is unavailable
Understanding of how to check
product/prepare product and how to
report wastage/unused product
Ability to prepare infusion site and draw
up product from single or multiple vials
and prime tubing
Demonstrated insertion of subcutaneous
catheter /checking for blood/what actions
to take if blood is present
Demonstrates appropriate aseptic
technique
Demonstrates accurate administration of
treatment, and removal and safe disposal
of needle
Demonstrates ability to accurately record
infusion treatment information in diary
Understanding of potential situations/
reactions which could result from the
infusion
Understanding of correct management of
any reactions to treatment
Form collated from contributions from Baxter, CSL Behring and Octapharma
16 / Immune Deficiency Foundation: Clinical Focus
Guardian (Please Circle One)
Competency
Demonstrated
Reinforced
Date:
Competent/Not Yet Competent
Caregiver
Competency
Mastered
Date:
Initials
C/NYC
Date:
Initials
C/NYC
Initials
IDF Services for Healthcare Professionals
IDF offers services and resources for healthcare professionals. Visit www.primaryimmune.org/healthcare-professionals
to learn more.
IDF Consulting Immunologist Program: A free service for physicians which provides the opportunity to consult with expert
clinical immunologists about patient specific questions and obtain valuable diagnostic, treatment and disease
management information regarding PI. Visit www.primaryimmune.org/consult
IDF & USIDNET LeBien Visiting Professor Program: Promotes improved knowledge by providing faculty at teaching
hospitals with a Visiting Professor with expertise in PI and offers Grand Rounds and clinical presentations at medical
institutions throughout the U.S.
IDF Online Continuing Education Course for Nurses (English): Primary Immunodeficiency Diseases and Immunoglobulin
Therapy: A free, 5-hour, U.S. accredited course for nurses that provides an update on PI, immunoglobulin therapies and
the nurse’s role with these therapies. Video Translations for Nurses in French, German, and Spanish are also available.
www.primaryimmune.org/healthcare-professionals/continuing-education-course-for-nurses
United States Immunodeficiency Network (USIDNET): USIDNET is a research consortium established to advance
research in the field of PI by maintaining a primary immunodeficiency disease registry, and providing education and
mentoring for young investigators. USIDNET, a program of the Immune Deficiency Foundation (IDF), is funded in part by
the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institutes of Health (NIH) an agency of
the Department of Health & Human Services.
IDF Medical Advisory Committee: Comprised of prominent immunologists to support the mission of IDF.
IDF Nurse Advisory Committee: Comprised of exceptional nurses to support the mission of IDF. Available as a resource for
nurses administering immunoglobulin therapy or treating patients with PI.
IDF Publications for Healthcare Professionals
All publications are available at no cost, and they can either be ordered, or downloaded and printed.
www.primaryimmune.org/idf-publications.
IDF Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency Diseases 3rd Edition
IDF Guide for Nurses on Immunoglobulin Therapy for Primary Immunodeficiency Diseases 3rd Edition
Clinical Focus on Primary Immunodeficiencies:
•
“Chronic Granulomatous Disease”
•
“Clinical Update in Immunoglobulin Therapy for Primary Immunodeficiency Diseases”
•
“Subcutaneous IgG Therapy in Immune Deficiency Diseases”
•
“Primary Humoral Immunodeficiency Optimizing IgG Replacement Therapy”
•
“The Clinical Presentation of Primary Immunodeficiency Diseases”
•
“Treatment and Prevention of Viral Infections in Patients with Primary Immunodeficiency Diseases”
•
“IgG Subclass Deficiency”
•
“Immunization Of The Immunocompromised Host”
IDF Resources for Patients and Families
IDF has numerous resources on primary immunodeficiency diseases for patients and families, including publications, peer
support programs, online networks and forums, educational programs, disease management tools, and much more. We
encourage you to visit www.primaryimmune.org to see the full spectrum of our offerings, and we urge you to order and
distribute our publications, all free of charge. If you have any questions or need additional information, please contact us
at 800-296-4433 or info@primaryimmune.org.
The Immune Deficiency Foundation, founded in 1980, is the national
patient organization dedicated to improving the diagnosis, treatment and
quality of life of persons with primary immunodeficiency diseases
through advocacy, education and research.
110 West Road | Suite 300 | Towson, Maryland 21204 | 800-296-4433 | www.primaryimmune.org | idf@primaryimmune.org